Decreased sarcoplasmic reticulum calcium content is responsible for defective excitation-contraction coupling in canine heart failure

Background-Altered excitation-contraction (E-C) coupling in canine pacing-induced heart failure involves decreased sarcoplasmic reticulum (SR) Ca uptake and enhanced Na/Ca exchange, which could be expected to decrease SR Ca content (Ca-SR) and may explain the reduced intracellular Ca (Ca-i) transient. Studies in other failure models have suggested that the intrinsic coupling between L-type Ca current (I-Ca,I-L) and SR Ca release is reduced without a change in SR Ca load, The present study investigates whether Ga-SR and/or coupling is altered in midmyocardial myocytes from failing canine hearts (F), Methods and Results-Myocytes were indo-1-loaded via patch pipette (37 degreesC), and Ca-i transients were elicited with voltage-clamp steps applied at various frequencies. I-Ca,I-L density was not significantly decreased in F, but steady-state Ca-i transients were reduced to 20% to 40% of normal myocytes (N). Ca-SR measured by integrating Na/Ca exchange currents during caffeine-induced release, was profoundly decreased in F, to 15% to 25% of N. When Ca-SR was normalized in F by preloading in 5 mmol/L external Ca before a test pulse at 2 mmol/L Ca, a normal-amplitude Ca-i transient was elicited, E-C coupling gain was dependent on Ca-SR but was affected similarly in both groups, indicating that intrinsic coupling is unaltered in F. Conclusions-A decrease in Ca-SR is sufficient to explain the diminished Ca-i transients in F, without a change in the effectiveness of coupling. Therefore, therapeutic approaches that increase Ca-SR may be able to fully correct the Ca handling deficit in heart failure.